Biomarker Tests for Molecularly Targeted Therapies — The Key to Unlocking Precision Medicine
As the promise and the pitfalls of precision medicine gain increasing attention,1,2 enthusiasm about the field has been heightened by a rapid reduction in the cost of high-throughput genomic sequencing and a dramatic increase in the identification of potential molecular targets for therapy. Biomarker tests for molecularly targeted therapies can help physicians to select the most effective therapy for a patient’s condition and avoid treatments that could be ineffective or harmful. If precision medicine is to reach its potential, such biomarker tests will have to be developed in a timely fashion.
Some observers, however, have expressed concern that these rapid developments have caused genomic data to accumulate at a rate that exceeds our ability to adequately capture, fully analyze, and properly interpret them. The medical armamentarium available to physicians seeking to tailor therapies to their patients’ conditions is expanding in parallel. Annual spending on molecularly targeted therapies for oncology in the United States now exceeds $10 billion, outpacing spending on conventional chemotherapies. In 2015 alone, the Food and Drug Administration approved 18 new agents for cancer, nearly all of which were based on the principles of precision medicine.
The degree to which physicians will be able to apply genomic information in selecting therapy that improves clinical care remains to be seen and will probably vary over the near term.3,4 The processes of identifying and validating biomarker tests and of developing and evaluating targeted therapies are complex. Potentially useful tests have not been adopted into clinical practice rapidly, in part because we lack common evidentiary standards for regulatory, clinical, coverage, and reimbursement decisions. Furthermore, clinical implementation will require the consistent collection and sharing of data on biomarker tests, treatments, and patient outcomes.5
The Institute of Medicine (IOM) has convened several expert committees over the past few years to consider a range of issues related to biomarkers, biomarker testing, genomics, and related disciplines. These efforts have highlighted the need for a systematic examination of all the challenges and opportunities associated with biomarker assays for molecularly targeted therapies. Most recently, the IOM assembled a Committee on Policy Issues in the Clinical Development and Use of Biomarkers for Molecularly Targeted Therapies (on which the authors served) to study and make recommendations about relevant regulatory, reimbursement, and clinical practice issues. The committee’s report (nas.edu/biomarkers), released in March, provides 10 specific but wide-ranging recommendations based on the premise that properly validated and implemented biomarker tests and targeted therapies hold considerable promise for enhancing the quality of patient care and improving meaningful clinical outcomes (see IOM Committee Recommendations for Advancing Appropriate Use of Biomarker Tests for Molecularly Targeted Therapies).
First and foremost, the committee calls for the development of common standards for assessing the utility of biomarker tests in the selection of targeted therapies and improvement of patient outcomes. Such standards would inform regulatory oversight of test development and approval, appropriate clinical adoption and utilization, and decisions about coverage and reimbursement. Interoperability and integration of electronic health records and laboratory information systems, ideally by means of a national database for health care providers and patients, would enhance the sustainable implementation and continuous evaluation of such tests. The committee further recommends that equitable access to biomarker tests and targeted therapies be ensured through patient and provider education, simplified and informative labeling, and supportive reimbursement policies.
The committee’s recommendations are meant to guide both the development of evidence supporting initial clinical application of biomarker tests and the ongoing assessment of their benefit. Given that the apparent value or benefit of biomarkers for a molecularly targeted therapy may vary considerably, a primary goal of the committee’s recommendations is to increase patients’ access to appropriate, accurate, reliable tests that can direct personalized or precision therapy.
The committee pursued its work against the backdrop of President Barack Obama’s Precision Medicine Initiative, which aims to empower clinicians, patients, and investigators to work together toward more personalized care and improved clinical outcomes and includes the development of a large patient cohort from which both clinical and “omics” data would be collected. Relevant congressional actions include the 21st Century Cures bill in the House of Representatives and companion bills in the Senate. In addition, President Obama has asked Vice President Joe Biden to take charge of a new Cancer Moonshot Initiative aimed at developing a large, interoperable, and fully integrated database to accelerate cancer discovery and innovation and at improving the delivery of such advances to patients and health care providers.
If it is developed and maintained in a rigorous, evidence-based fashion with well-designed and well-executed studies, precision medicine could rapidly advance the care of patients with cancer and other diseases by tailoring treatment to individual patients’ conditions and improving clinical outcomes and quality of life, while reducing costs by averting the use of ineffective or harmful therapies. However, precision medicine comes with the methodologic challenges associated with small target populations, as well as the reimbursement challenges associated with an increasingly value-sensitive health care delivery environment. Moreover, there is potential for the unintended consequence of intensifying disparities in access to advanced health care services, including biomarker testing and molecularly targeted therapies.
Before such biomarker tests become part of standard care, it is essential to establish that such tests are accurate and reliable (have analytic validity), are associated with the disease and outcome of interest (clinical validity), and actually lead to improved patient outcomes as compared with standard treatment (clinical utility). This process starts with the establishment of the reliability, accuracy, and precision of the test based on rigorous laboratory studies. Molecularly targeted agents should be administered only if a specific biomarker that predicts the effectiveness of the therapy is known to be present on the basis of a validated assay. When the effectiveness and safety of a therapy depends on the status of a biomarker, the test becomes as important as the treatment for optimal patient care.5
There is also a need for consensus on the evidence required to adequately establish clinical utility for initial use; the assessment of utility may change over time, as evidence accumulates and new tests and treatments are developed. The line between clinical research and clinical care is likely to be blurred in the era of precision medicine. We believe it will be critical for health systems and individual providers to share in the responsibility for data capture and integration until there is sufficient evidence to determine whether a given test has actual clinical utility. Payers will also have to share in the responsibility for coverage and reimbursement as the evidence is refined.
Finally, everyone involved will have to work to ensure that patients have fair and equitable access to promising as well as established biomarker tests for molecularly targeted therapies. A national initiative involving not only clinicians and laboratory scientists but also experts in informatics could continuously capture, catalogue, and annotate data on biomarkers and targeted therapies and make them available to regulators, providers, payers, and patients who want to take a more active role in shared decision making. We believe these steps will enable precision medicine to fulfill its potential for improving patient care and clinical outcomes.
June 1, 2016DOI: 10.1056/NEJMp1604033